Anxiogenic, not psychotogenic, properties of the partial inverse benzodiazepine receptor agonist FG 7142 in man

In Vitro and in Vivo Properties of 3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA Receptor α5 Subtype-Selective Inverse Agonist

“…The data showing that MRK-016 is not anxiogenic or proconvulsant and does not produce kindling are consistent with previous data obtained with ␣5IA . These data, taken together with those from studies conducted with the ␣5 binding-selective compounds L-655,708 and RO4938581 (Atack et al, 2006a;Ballard et al, 2009), demonstrate that in preclinical species inverse agonism at the ␣5 subtype is not associated with the liabilities associated with nonselective inverse agonists, such as FG-7142 (Dorow et al, 1983;Horowski and Dorow, 2002).…”

“…The reason for the poor tolerability of MRK-016 in the 2-mg multiple-dose study is unclear but is presumably unrelated to the mechanism because there was no reduction in tolerability in the multiple-compared with single-dose studies of ␣5IA (Atack, 2009). One of the unblinded AEs observed in the 2-mg multiple-dose study was anxiety, but this was not comparable with the waves of anxiety reported after dosing with the nonselective partial inverse agonist FG-7142 (Dorow et al, 1983;Horowski and Dorow, 2002). It is important to note that anxiety was not reported as an AE in either of the single-dose studies performed with MRK-016 in young or elderly volunteers, and neither was it observed in the single-or multiple-dose studies of ␣5IA carried out in young and elderly volunteers (Atack, 2009).…”

“…Hence, benzodiazepine site agonists possess a variety of pharmacological actions in human, including anxiolytic, sedative, myorelaxant, anticonvulsant, and cognition-impairing activities (Argyropoulos and Nutt, 1999;Buffett-Jerrott and Stewart, 2002), whereas inverse agonists are anxiogenic and convulsant or proconvulsant and also enhance vigilance and improve cognitive performance in preclinical species (Sieghart, 2006). Unfortunately, the anxiogenic and proconvulsant properties of nonselective inverse agonists have precluded their clinical use as cognition and/or vigilance enhancers (Dorow et al, 1983;Horowski and Dorow, 2002). Clearly, however, a compound that retained the cognition-enhancing properties yet was devoid of the anxiogenic and proconvulsant liabilities would offer the potential for clinical utility.…”

GABA Deficits Enhance the Psychotomimetic Effects of Δ9-THC

“…However, unlike flumazenil, which blocks the effects of BZR agonists but lacks intrinsic pharmacological effects (Hunkeler et al, 1981), inverse agonists interfere with the function of the BZR in coupling the GABA A receptor and chloride channel, and have intrinsic pharmacological effects opposite to those of BZR agonists (Tallman and Gallager, 1985). For example, the BZR inverse agonist FG-7142 is anxiogenic in healthy human subjects (Dorow et al, 1983;Horowski and Dorrow, 2002). BZR inverse agonist drugs bind to extrasynaptic GABA A receptors (Liang et al, 2004).…”

AMPA Receptor Potentiation can Prevent Ethanol-Induced Intoxication

“…Impairments in rotorod performance following 1.5 g/kg ethanol are also reversed via prior infusion of Ro15-4513 into the striatum (Meng and Dar, 1994) and motor cortex (Barwick and Dar, 1998). However, Ro15-4513 has not been tested clinically and the related benzodiazepine partial inverse agonist, FG7142, causes intense anxiety states in healthy volunteers (Horowski and Dorow, 2002). In contrast, LY451395 is well tolerated in healthy volunteers and elderly patients (Jhee et al, 2006) rendering AMPA potentiators a more attractive and practical candidate for further development as a possible pharmacological intervention strategy.…”